Advanced human in vitro models of pain

Chronic pain is a widespread and debilitating condition affecting millions of people worldwide. It is a frequent manifestation of many diseases, increasing with age and multi-morbidity. Existing pain treatments, including opioid medications, often provide inadequate relief and can lead to harms such as dependency. Recent advances have provided new insights into pain mechanisms and new opportunities for developing pain treatments. However, one of the biggest challenges in chronic pain research is the complexity of the pain system, which involves multiple cell types—including neural, immune, and vascular cells—all interacting in a dynamic way. Current models fail to accurately reflect this complexity, representing a critical bottleneck that is impeding the development of effective treatments. There is an urgent need for human-specific models of the pain pathway that can capture the distinct disease processes of different pain conditions and act as a crucial bridge to translation for novel therapeutics targeting these mechanisms. This project seeks to harness recent progress to develop innovative human models that better replicate complex pain pathways. We will establish the cellular models and then induce pain-like states in the models, with a focus on neuropathic pain and osteoarthritis pain. The models we develop will be carefully validated and we will disseminate protocols to maximise adoption and impact. Our specific objectives include: Progress human induced pluripotent stem cell (iPSC) models of sensory neurons grown in 2D and 3D organoid cultures to better capture pain sensory neuron diversity and improve maturity Develop our native human dorsal root ganglia culture platform obtained from neurosurgical patients. Model the multi-cellular interactions involved in pain through vascularisation and incorporation of immune cells and signals. Recapitulate pain-like cellular and molecular states of neuropathic pain and osteoarthritis pain Develop machine learning processes to map human in vitro model assay end-points with clinically relevant pain states and response to drugs Engage throughout the project with end-users to help shape and select models that are fit for purpose and will be adopted by researchers for basic science or in drug discovery workflows This research has wide-ranging applications that could transform chronic pain treatment and research. Pharmaceutical companies will be able to use these models to test new pain medications in a system that better reflects human biology, increasing the chances of successful clinical trials. By providing a more effective alternative to animal models, this project supports efforts to replace animal testing in medical research. By linking human in vitro models to patient clinical features, the research will help identify why some individuals respond differently to pain medications, paving the way for tailored treatments. The insights gained from these models will improve our fundamental understanding of pain pathogenesis, helping to uncover new biological pathways that could be targeted for treatment. This project will be carried out in collaboration with leading academic institutions, industry partners, and regulatory bodies to ensure that the findings are widely adopted. By working closely with clinicians and patient groups, the research will remain patient-focused, addressing the real-world needs of people living with chronic pain. Our programme involves and trains researchers at all levels (students to emerging leaders to senior PIs), ensuring we address capabilities and skills gap for this field. Ultimately, this work has the potential to significantly advance how chronic pain is studied, offering a more successful path to much needed effective treatment.